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In a yeast two-hybrid screening assay, a splicing variant of interferon (IFN) regulatory factor 3 (IRF3) was found to interact with the BGLF4 protein. This interaction was defined further by coimmunoprecipitation in transfected cells and glutathione<jats:italic>S<\/jats:italic>-transferase (GST) pull-down in vitro. Using reporter assays, we show that BGLF4 effectively suppresses the activities of the poly(I:C)-stimulated IFN-\u03b2 promoter and IRF3-responsive element. Moreover, BGLF4 represses the poly(I:C)-stimulated expression of endogenous IFN-\u03b2 mRNA and the phosphorylation of STAT1 at Tyr701. In searching for a possible mechanism, BGLF4 was shown not to affect the dimerization, nuclear translocation, or CBP recruitment of IRF3 upon poly(I:C) treatment. Notably, BGLF4 reduces the amount of active IRF3 recruited to the IRF3-responsive element containing the IFN-\u03b2 promoter region in a chromatin immunoprecipitation assay. BGLF4 phosphorylates GST-IRF3 in vitro, but Ser339-Pro340 phosphorylation-dependent, Pin1-mediated downregulation is not responsible for the repression. Most importantly, we found that three proline-dependent phosphorylation sites at Ser123, Ser173, and Thr180, which cluster in a region between the DNA binding and IRF association domains of IRF3, contribute additively to the BGLF4-mediated repression of IRF3(5D) transactivation activity. IRF3 signaling is activated in reactivated EBV-positive NA cells, and the knockdown of BGLF4 further stimulates IRF3-responsive reporter activity. The data presented here thus suggest a novel mechanism by which herpesviral protein kinases suppress host innate immune responses and facilitate virus replication.<\/jats:p>","DOI":"10.1128\/jvi.01099-08","type":"journal-article","created":{"date-parts":[[2008,12,4]],"date-time":"2008-12-04T01:55:23Z","timestamp":1228355723000},"page":"1856-1869","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":141,"title":["Epstein-Barr Virus BGLF4 Kinase Suppresses the Interferon Regulatory Factor 3 Signaling Pathway"],"prefix":"10.1128","volume":"83","author":[{"given":"Jiin-Tarng","family":"Wang","sequence":"first","affiliation":[{"name":"Graduate Institute and Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-Lian","family":"Doong","sequence":"additional","affiliation":[{"name":"Graduate Institute and Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Chun","family":"Teng","sequence":"additional","affiliation":[{"name":"Graduate Institute and Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Pei","family":"Lee","sequence":"additional","affiliation":[{"name":"Graduate Institute and Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Hwa","family":"Tsai","sequence":"additional","affiliation":[{"name":"Graduate Institute and Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-Ru","family":"Chen","sequence":"additional","affiliation":[{"name":"Graduate Institute and Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.20.10995-11006.2004"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02674-05"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.25.11657"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.13.5380-5388.2005"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.3.1202-1211.2004"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1534570100"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.12.7673-7681.2005"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2005.06.014"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.73.10.8857-8866.1999"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.8.4185-4196.2004"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.7.8.2745-2752.1987"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.74.7.3093-3104.2000"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-80-2-447"},{"key":"e_1_3_2_15_2","first-page":"3984","volume":"83","year":"2008","unstructured":"Cl\u00e9ment, J. 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